Reprint: Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys

TLDR

Recombinant human GDNF is a potent neuronal growth factor being explored for Parkinson’s disease, and prior nonclinical studies have not reported cerebellar toxicity. The study aimed to evaluate the safety of six‑month intraputamenal infusion of r‑metHuGDNF in rhesus monkeys to support clinical trials for Parkinson’s disease. Six to nine monkeys per sex received continuous unilateral intraputamenal infusion of 0, 15, 30, or 100 µg/day r‑metHuGDNF at 150 µl/day for six months, with some animals undergoing a three‑month recovery period. At 100 µg/day, animals showed decreased food intake and body weight, meningeal thickening at 30 and 100 µg/day, and multifocal cerebellar Purkinje cell loss in four monkeys, suggesting a dose‑dependent toxicity that warrants further investigation.

Abstract

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson’s disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6–9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 μg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 μl/day flow rate) for 6 months; a subset of animals (2–3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 μg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 μg/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-μg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.